Associations between white matter hyperintensity burden, cerebral blood flow and transit time in small vessel disease: an updated meta-analysis

Abstract

Cerebral small vessel disease is a major contributor to stroke and dementia, characterised by white matter hyperintensities (WMH) on neuroimaging. WMH are associated with reduced cerebral blood flow (CBF) cross-sectionally, though longitudinal associations remain unclear. We updated a 2016 meta-analysis, identifying 30 studies, 27 cross-sectional (n=2956) and 3 longitudinal (n=440), published since 2016. Cross-sectionally, we meta-analysed 10 new studies with 24 previously reported studies, total 34 (n=2180), finding lower CBF to be associated with worse WMH burden (mean global CBF: standardised mean difference: -0.45, 95% confidence interval (CI): -0.64,-0.27). Longitudinally, the association of baseline CBF with WMH progression varied: the largest study (5 years, n=252) found no associations, while another small study (4.5 years, n=52) found that low CBF in the periventricular WMH penumbra predicted WMH progression. We could not meta-analyse longitudinal studies due to different statistical and methodological approaches. We found lower CBF within WMH compared to normal appearing white matter (novel meta-analysis; 5 cross-sectional studies; n=295; SMD: -1.51, 95% CI: -1.94,-1.07). These findings highlight that relationships between resting CBF and WMH are complex and that more longitudinal studies analysing regional CBF and subsequent WMH change are required to determine the role of CBF in small vessel disease progression.

Sex differences in Cerebral Small Vessel Disease: a systematic review and meta-analysis

“…12 Current databases. Articles from four recent systematic reviews [13][14][15][16] that met our inclusion criteria (see below) were included. These systematic reviews provided a large publication sample that had already been screened against objective criteria, quality assessed and conducted according to PRISMA standards (Table 1).…”

“…To explore the most recent research including participants with SVD, an independent database search was also carried out. The search strategy was modified from a published protocol 16 to identify studies including participants with clinical (stroke or cognitive presentations) or non-clinical presentations of sporadic or monogenic SVD (e.g. CADASIL) ischemi* or ischaemi* or silent or microscopic) adj3 lesion*).ti,ab.).…”

“…Quality assessment and publication bias. Quality assessment was carried out as in a previously published study 16 , rated on a scale from 0-8 according to STROBE guidelines. The median and IQR of the quality score of the included studies were calculated.…”

Cerebral Vascular Dysfunctions Detected in Human Small Vessel Disease and Implications for Preclinical Studies

“…However, evidence for low CBF predating SVD lesions in humans is limited. Cross-sectionally, patients with worse WMHs had lower resting CBF, but excluding studies with poorly age-matched controls and patients with dementia removed the association between WMHs and low CBF (63,64). Low CBF predates symptom onset in AD by several years (65) and separately predicts accelerated brain volume loss (66), potentially confounding studies of SVD and CBF.…”

“…Of seven longitudinal studies of WMHs and CBF, the largest studies found that low baseline CBF did not predict worsening WMHs (64) but that worse baseline WMHs predicted falling CBF (67). Unfortunately, many studies did not account for vascular risk factors, exaggerating any apparent difference in CBF between the patients with WMHs and controls.…”